VEGFR Inhibitors for Uterine Metastatic Perivascular Epithelioid Tumors (PEComa) Resistant to mTOR Inhibitors. A Case Report and Review of Literature.

Uterine perivascular epithelioid cell tumors (PEComas) are rare neoplasms. PI3K/AKT/mTOR pathway upregulation is critical for their pathogenesis and is often associated with TSC1/TSC2 inactivation. Although first line mTOR inhibitors are an effective treatment, metastatic PEComas eventually progress. A 53-year-old woman presented a 4-month history of post-menopausal vaginal bleeding. Clinical and radiological examination detected a uterine mass and a single S1 bone lesion. The patient underwent a radical hysterectomy and bone biopsy. The anatomopathological evaluation concluded to an oligo-metastatic uterine PEComa. The tumor harbored a heterozygous deletion of 9q34 that contains the TSC1 gene. Concerning the primary lesion, the resection was complete and the single bone metastasis was treated with radiotherapy. Three months later, the patient presented bone, lung and subcutaneous metastatic progression. An everolimus and denosumab treatment was initiated. After 2 years of treatment, a clinically significant bone, lung and subcutaneous progression was detected. Following a literature review of the possible therapeutic options, we initiated a second line treatment by pazopanib. This treatment resulted in regression of the subcutaneous lesions and stability of lung and bone metastases. In this challenging, rare setting, our report suggests single agent, anti-angiogenic, tyrosine kinase inhibitor to be effective as second line treatment of metastatic uterine PEComa progressing on mTOR inhibitors

A Locally Advanced Endometrioid Adenocarcinoma Arising from Vaginal Endometriosis: Management and Review of the Literature

Endometrioid adenocarcinoma associated with endometriosis at extrauterine or extraovarian localization is a rare entity. Often presenting with local spread without nodal and distant metastasis, this entity has no specific staging system nor treatment guidelines. In the case of nodal and distant spread, the treatment decision requires personalization. In this article, we present the diagnosis and surgical and systemic treatment of a 56-year-old woman diagnosed with an endometriosis-associated advanced endometrioid adenocarcinoma of the vagina with nodal involvement. Following an extensive review of the scarce data reported to guide the treatment choices in this rare setting, we proposed a multidisciplinary treatment with laparoscopic surgical cytoreduction, four cycles of adjuvant chemotherapy with carboplatin and paclitaxel, and radiotherapy with brachytherapy. Due to an anaphylactic reaction on the first administration, paclitaxel was replaced with nab-paclitaxel. Despite many negative prognostic factors, the patient is free from relapse after 48 months. We report the case of a locally advanced endometrioid adenocarcinoma associated with endometriosis of the vagina, with pelvic nodal spread, and the relevant literature review of similar cases

Heavy/light chain (HLC) and free light chain (FLC) analysis allow sensitive monitoring of multiple myeloma patients and AID detection of clonal changes

peer reviewe

Cloning and sequencing of the low-affinity penicillin-binding protein 3r-encoding gene of Enterococcus hirae S185: modular design and structural organization of the protein.

The clinical isolate Enterococcus hirae S185 has a peculiar mode of resistance to penicillin in that it possesses two low-affinity penicillin-binding proteins (PBPs): the 71-kDa PBP5, also found in other enterococci, and the 77-kDa PBP3r. The two PBPs have the same low affinity for the drug and are immunochemically related to each other. The PBP3r-encoding gene has been cloned and sequenced, and the derived amino acid sequence has been compared by computer-assisted hydrophobic cluster analysis with that of the low-affinity PBP5 of E. hirae R40, the low-affinity PBP2' of Staphylococcus aureus, and the PBP2 of Escherichia coli used as the standard of reference of the high-M(r) PBPs of class B. On the basis of the shapes, sizes, and distributions of the hydrophobic and nonhydrophobic clusters along the sequences and the linear amino acid alignments derived from this analysis, the dyad PBP3r-PBP5 has an identity index of 78.5%, the triad PBP3r-PBP5-PBP2' has an identity index of 29%, and the tetrad PBP3r-PBP5-PBP2'-PBP2 (of E. coli) has an identity index of 13%. In spite of this divergence, the low-affinity PBPs are of identical modular design and possess the nine amino acid groupings (boxes) typical of the N-terminal and C-terminal domains of the high-M(r) PBPs of class B. At variance with the latter PBPs, however, the low-affinity PBPs have an additional approximately 110-amino-acid polypeptide stretch that is inserted between the amino end of the N-terminal domain and the carboxy end of the membrane anchor. While the enterococcal PBP5 gene is chromosome borne, the PBP3r gene appears to be physically linked to the erm gene, which confers resistance to erythromycin and is known to be plasmid borne in almost all the Streptococcus spp. examined

So-Called Serous Carcinoma of the Uterine Cervix with BRCA2 Mutation: Case Report and Review of the Literature.

Serous carcinoma of the uterine cervix (SCUC) is now believed to be a morphological variant of an HPV-associated endocervical adenocarcinoma or a metastasis from a serous carcinoma of the upper tract. In terms of mutational status as detected by next-generation sequencing (NGS), this controversial entity has not been characterized yet. We describe the case of a patient with a carcinoma categorized as stage IVB SCUC, initially treated with carboplatin, paclitaxel, and bevacizumab, followed by maintenance with bevacizumab. After locoregional progression, radiotherapy was administered. Unfortunately, further progression was observed, and carboplatin was resumed. Considering the presence of a BRCA2 mutation as detected by NGS, treatment with a PARP inhibitor (olaparib) was decided and allowed disease control for 6 months. We believe that BRCA mutation may be systematically searched in patients suffering from carcinomas formerly referred to as SCUC and that targeted treatments should be considered

Histological regression of peritoneal metastases of recurrent tubo-ovarian cancer after systemic chemotherapy.

Post-treatment histological regression of peritoneal metastases (PM) is a new and potentially important predictor of oncological outcomes. Histology of PM from adnexal origin is usually evaluated by the Chemotherapy Response Score (CRS). The aim of this preliminary study was to quantify the response of PM of recurrent tubo-ovarian cancer (TOVC) after systemic chemotherapy by using the recently validated Peritoneal Regression Grading System (PRGS) and compare it with CRS. Correlation with per operative evaluation through Peritoneal Cancer Index (PCI) was performed. Retrospective cohort study of all consecutive patients with recurrent PM from TOVC undergoing surgery after prior systemic chemotherapy from January 2015 to March 2019. Biopsies were assessed with the four-scale PRGS. Thirty-eight patients were included. Patients had a median of 2 (range 1-2) lines and 12 (range 3-18) cycles of prior systemic chemotherapy. Overall mean (SD) PRGS was 2.3 (±1.1). Of the patients, 26% (10) had complete response (PRGS 1), 40% (15) had major response (PRGS 2), 26% (10) minor response (PRGS 3), and 8% (3) had no response (PRGS 4). Mean PRGS was positively correlated with the Peritoneal Cancer Index (ρ = 0.5302, p = 0.0003) and inversely correlated with CRS (ρ = -0.8403, p < 0.0001). No correlation was highlighted between mean PRGS and overall survival (ρ = -0.0195, p = 0.9073). CRS and mean PRGS correlated with each other. Histological response of PM after systemic chemotherapy was quantifiable and variable. The role of PRGS for the evaluation of treatment response and as potential surrogate marker for oncological outcomes is part of ongoing and planned research

Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study

High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland–Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from −0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the ‘ideal’ sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions